Journal article
ERK2-regulated TIMP1 Induces Hyperproliferation of K-Ras G12D-Transformed Pancreatic Ductal Cells
Neoplasia (New York, N.Y.), Vol.15(4)
01 Apr 2013
Abstract
Pancreatic ductal adenocarcinoma (PDAC) commonly contains a mutation in K-RasG12D and is characterized by a desmoplastic reaction composed of deregulated, proliferating cells embedded in an abnormal extracellular matrix (ECM). Our previous observations imply that inhibiting the MAPK-ERK2 kinase signal pathway reverses an MMP-1 specific invasive phenotype. Here we investigated the specific genes downstream of MAPK-ERK2 responsible for the hyperproliferative abilities of human and murine primary ductal epithelial cells (PDCs) within an ECM. Compared with control, DNA synthesis and total cell proliferation was significantly increased in human PDCs harboring the PDAC-common p53, Rb/p16INK4a, and K-RasG12D mutations. Both of these effects were readily reversed following small-molecule inhibition or lentiviral silencing of ERK2. Microarray analysis of PDCs in 3D culture revealed a unique, MAPK-influenced gene signature downstream of K-RasG12D. Unbiased hierarchical analysis permitted filtration of tissue inhibitor of matrix metalloproteinase (TIMP)-l. Pancreatic cells isolated from Pdxl-Cre; LSL-KrasG12D/+ mutated mice exhibit increased TIMP1 RNA transcription as compared to wild type littermate controls. Analyses of both 3D, in vitro human K-RasG12D PDCs and data mining of publicly annotated human pancreatic datasets correctively indicate increased levels of TIMP1 RNA. While silencing TIMP1 did not significantly effect PDC proliferation, exogenous addition of human recombinant TIMP-1 significantly increased proliferation, but only in transformed K-RasG12D PDCs in 3D. Overall, TIMP1 is an upregulated gene product and a proliferative inducer of K-RasG12D mutated PDCs via the ERK2 signaling pathway.
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Details
- Title
- ERK2-regulated TIMP1 Induces Hyperproliferation of K-Ras G12D-Transformed Pancreatic Ductal Cells
- Creators
- G BottaM ReichertM J ReginatoS HeegA RustgiP Lelkes
- Publication Details
- Neoplasia (New York, N.Y.), Vol.15(4)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Identifiers
- 991020112126104721